Enabling a learning healthcare system with automated computer protocols that produce replicable and personalized clinician actions.

Clinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention-the starting point for delivery of "All the right care, but only the right care," an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.

Loss of ASXL1 expression is associated with lymph node metastasis in colorectal cancer.

CONTEXT: The function of ASXL1 in colorectal cancer (CRC) has not been investigated yet. AIMS: The purpose of this study was to investigate the clinicopathological and prognostic impact of ASXL1 expression on CRC. SETTINGS AND DESIGN: The intensity of expression was scored as 0-3, and the extent of staining was scored as 0-4, based on the percentage of positive cells. The immunoreactivity score (IRS) was calculated by multiplying the two scores. MATERIALS AND METHODS: We performed immunohistochemical staining of ASXL1 using tissue microarrays of 408 CRCs, 46 normal colonic mucosae, 48 adenomas, and 92 metastatic lymph nodes. STATISTICAL ANALYSIS USED: Clinicopathological variables were compared using Fisher's exact test, χ2-test, or unpaired Student's t-test, depending on the nature of the data. RESULTS: A negative expression of ASXL1 was observed in 10.9% of normal mucosae, 27.1% of adenomas, 55.6% of adenocarcinomas, and 71.7% of metastatic lymph nodes (P < 0.001). With respect to the IRS cut-off score, lymph node metastasis and lymphatic invasion were more frequent in the IRS 0-6 group than in the IRS 8-12 group (56.3% vs. 33.3%, P = 0.034; 56.0% vs. 33.3%, P = 0.035). The 5-year disease-free survival rate was significantly lower in patients with IRS 0-6 group than those with IRS 8-12 group (78.7 ± 2.5 vs. 100%, P = 0.034). CONCLUSION: ASXL1 might act as a tumor suppressor in CRC. The loss of ASXL1 expression might be associated with lymph node metastasis and lymphatic invasion in CRC.

Association of common variations of 8q24 with the risk of prostate cancer in Koreans and a review of the Asian population.

UNLABELLED: What's known on the subject? and What does the study add? The association between subjects with the genetic variation of 8q24 and the risk of development of prostate cancer in Korean men was found. As a result of haplotype analysis, [AGC] and [CTA] carriers showed a significant association with prostate cancer risk. This is clinically meaningful as an initial study on genetic susceptibility to prostate cancer in Korean men and the first report of 8q24 haplotypes in an Asian population. OBJECTIVE: To determine the association between genetic variation of 8q24 with prostate cancer risk in Korean men. PATIENTS AND METHODS: With a hospital-based case-control study design, we enrolled 194 patients with prostate cancer and 169 healthy controls from visitors for cancer screening. DNA samples were obtained from peripheral blood for the analysis of single nucleotide polymorphisms (SNPs). Three SNPs of 8q24, including rs16901979, rs6983267, and rs1447295, were genotyped on cases and controls. RESULTS: The subjects with the rs1447295 CA or AA genotype had a higher risk of prostate cancer than the CC genotype. The A allele at SNP rs1447295 was associated with the incidence of prostate cancer. The rs16901979 CA genotype carriers had a higher risk of prostate cancer than the CC genotype. Individuals with the [AGC] and [CTA] haplotypes had a significantly increased risk of prostate cancer compared with the [CTC] haplotype ([AGC] with adjusted odds ratio [OR] 1.79; 95% confidence interval [CI] 1.09-2.96; P = 0.022; [CTA] with adjusted OR 5.17; 95% CI 2.40-11.15; P < 0.001). CONCLUSIONS: The genetic variation of 8q24 is associated with the risk of prostate cancer in Korean men. Individuals with the [AGC] and [CTA] haplotypes had a significant association with prostate cancer risk.

A replicable method for blood glucose control in critically Ill patients.

CONTEXT: To ensure interpretability and replicability of clinical experiments, methods must be adequately explicit and should elicit the same decision from different clinicians who comply with the study protocol. OBJECTIVE: The objective of this study was to determine whether clinician compliance with protocol recommendations exceeds 90%. DESIGN: We developed an adequately explicit computerized protocol (eProtocol-insulin) for managing critically ill adult patient blood glucose. We monitored clinician compliance with eProtocol-insulin recommendations in four intensive care units in four hospitals and compared blood glucose distributions with those of a simple clinical guideline at one hospital and a paper-based protocol at another. All protocols and the guideline used intravenous insulin and 80 to 110 mg/dL (4.4-6.1 mmol/L) blood glucose targets. SETTING: The setting for this study was four academic hospital intensive care units. PATIENTS: This study included critically ill adults requiring intravenous insulin. INTERVENTION: Intervention used in this study was a bedside computerized protocol for managing blood glucose. MAIN OUTCOME MEASURE: The main outcome measure was clinician compliance with eProtocol-insulin recommendations. RESULTS: The number of patients was 31 to 458 and the number of blood glucose measurements was 2,226 to 19,925 among the four intensive care units. Clinician compliance with eProtocol-insulin recommendations was 91% to 98%. Blood glucose distributions were similar in the four hospitals (generalized linear model p = .18). Compared with the simple guideline, eProtocol-insulin glucose measurements within target increased from 21% to 39%, and mean blood glucose decreased from 142 to 115 mg/dL (generalized linear model p < .001). Compared with the paper-based protocol, eProtocol-insulin glucose measurements within target increased from 28% to 42%, and mean blood glucose decreased from 134 to 116 mg/dL (generalized linear model p = .001). CONCLUSIONS: The 91% to 98% clinician compliance indicates eProtocol-insulin is an exportable instrument that can establish a replicable experimental method for clinical trials of blood glucose management in critically ill adults. Control of blood glucose was better with eProtocol-insulin than with a simple clinical guideline or a paper-based protocol.

MYH, OGG1, MTH1, and APC alterations involved in the colorectal tumorigenesis of Korean patients with multiple adenomas.

This study was done to characterize base excision repair (BER) genes and adenomatous polyposis coli (APC) alterations in the tumorigenesis of multiple colorectal adenomas in Korean patients. In total, 217 adenomas (mean number = 10) and 117 cancers were available from 143 patients. The heterozygous genotype of OGG1 c.1-18G>T was closely associated with multiple adenoma families (P < 0.001), while MYH A359V mutation exhibited a tendency (P = 0.053). MYH R170G mutation was exclusively identified in one patient. The G:C>T:A transversion or attenuated familial adenomatous polyposis (AFAP) mutations of APC was identified in the specific genotypes of BER variants. Tubular adenomas or adenomas with none-to-mild dysplasia were significantly associated with polymorphic genotypes of OGG1 IVS4-15 and S326C. In addition, large and pedunculated adenomas were more frequent in patients with G:C>T:A transversion and AFAP mutations of APC, respectively. However, BER variants were not associated with mismatch repair or altered p53 protein expression. Conclusively, two novel mutations of MYH and a novel OGG1 polymorphism seemed to be associated with multiple colorectal adenomas in Korean families, differing from those in other ethnic groups. Some BER variants involved in specific APC mutations are associated with characteristics of histogenesis other than altered mismatch repair or p53 pathway.

Efficacy of 3-dimensional endorectal ultrasonography compared with conventional ultrasonography and computed tomography in preoperative rectal cancer staging.

BACKGROUND: This study was performed to verify reports of the decreased accuracy of endorectal ultrasonography (EUS) in preoperative staging of rectal cancer, and to compare the efficacy of 3-dimensional (3D) EUS with that of 2-dimensional (2D) EUS and computed tomography (CT). METHODS: Eighty-six consecutive rectal cancer patients undergoing curative surgery were evaluated by 2D EUS, 3D EUS, and CT scan. RESULTS: The accuracy in T-staging was 78% for 3D EUS, 69% for 2D EUS, and 57% for CT (P < .001-.002), whereas the accuracy in evaluating lymph node metastases was 65%, 56%, and 53%, respectively (P < .001-.006). Examiner errors were the most frequent cause of misinterpretation, occurring in 47% of 2D EUS examinations and in 65% of 3D EUS examinations. By eliminating examiner errors, the accuracy rates in T-staging and lymph node evaluation could be improved to 88% and 76%, respectively, for 2D EUS, and to 91% and 90%, respectively, for 3D EUS. Conical protrusions along the deep tumor border on 3D images were correlated closely with infiltration grade, advanced T-stage, and lymph node metastasis. CONCLUSIONS: We found that 3D EUS showed greater accuracy than 2D EUS or CT in rectal cancer staging and lymph node metastases. Concrete 3D images based on tumor biology appear to provide more accurate information on tumor progression.

Hepatic arterial infusion alternating with systemic chemotherapy in patients with non-resectable hepatic metastases from colorectal cancer.

BACKGROUND AND AIM: Hepatic arterial infusion (HAI) chemotherapy has a number of limitations, including a low rate of complete response and frequent extrahepatic recurrence, in colorectal cancer patients with non-resectable hepatic metastases. METHODS: Twenty-nine colorectal cancer patients with non-resectable hepatic metastases were consecutively enrolled for HAI alternating with systemic chemotherapy (HA + SC group). The protocol comprised six cycles of alternating HAI (5-FU + leucovorin for 14 days, and mitomycin C on the first day) and systemic chemotherapy (5-FU + leucovorin). Colorectal cancer patients with two or more hepatic metastases treated using hepatic resection and systemic chemotherapy (HR + SC group) were selected as a comparative group. RESULTS: Within the HA + SC group, complete response was achieved in eight patients (28%), whereas 13 patients (45%) showed progressive disease. Six of the eight patients with complete response lived for more than 38 months. Extrahepatic recurrences were more frequent in the HR + SC group than the HA + SC group (47 vs 21%, P = 0.024). The two groups did not differ with respect to overall and hepatic progression-free survival (P = 0.947 and 0.444, respectively), displaying median +/- SE values of 38 +/- 7 and 20 +/- 3 months in the HA + SC group, and 39 +/- 9 and 33 +/- 14 months in the HR + SC group, respectively. One patient in each group experienced toxic hepatitis, and sclerosing cholangitis occurred in one patient of the HA + SC group. Other complications were mostly grade 1 or 2. CONCLUSIONS: HAI alternating with systemic chemotherapy led to a promising response and hepatic progression-free survival, possibly reducing extrahepatic recurrence in colorectal cancer patients with non-resectable liver metastases.

Genetic and pathologic changes associated with lymphovascular invasion of colorectal adenocarcinoma.

Lymphovascular invasion (LVI) is a biological manifestation of aggressive behavior in colorectal cancer. This study sought to identify and examine the association between genetic and pathologic alterations implicated in this invasive tumor progression. We consecutively recruited 81 and 79 colorectal cancer patients with and without LVI, respectively. Biological changes were evaluated by clinicopathological parameters together with CEA and E-cadherin expressions using immune staining. Allelic loss or MSI was examined using 10 microsatellite markers on chromosomes 10, 16, 18, and TGFbetaRII, possibly associated with colorectal cancer. The germline mutation of BMPR1A and SMAD4 was also sought. Tumor stage and lymph node metastasis were significantly greater in patients with LVI tumor than without it (P < 0.001). Decreased CEA expression was closely correlated with allelic loss or MSI at D16S421, D18S46, and D18S474 (P = 0.004-0.047). Allelic loss at D10S14 was specific to LVI tumors (P = 0.007). Using multivariate analysis, allelic loss at D18S46 significantly correlated with histological differentiation (P = 0.02). In addition, allelic loss and MSI at D18S474, histological differentiation, and expression of CEA and E-cadherin were closely associated with the progression of LVI (P = 0.005-0.049). However, no germline mutation in BMPR1A or SMAD4 was detected in all patients regardless of LVI status. In summary, in a subset of colorectal cancers, histological differentiation and expression of CEA or E-cadherin appear to determine aggressive behavior such as LVI. These changes are closely associated with chromosomal alterations at 10q22-23, 16q22 and 18q21, which carry several tumor suppressor genes.

Experimental radioimmunoguided surgery for peritoneal metastases of gastric cancer using anticarcinoembryonic antigen-specific T84.66 F(ab')2.

PURPOSE: In gastric cancer, peritoneal dissemination is the most frequent cause of the noncurative resection and recurrence after curative resection. We therefore evaluated the feasibility of radioimmunoguided surgery (RIGS) in the treatment of peritoneal metastases of gastric cancer and the use of anti-CEA-specific T84.66 F(ab')2 as an efficient immune agent. METHODS: Two human gastric cancer cell lines, MKN45 and RF48, were intraperitoneally xenografted into nude mice, which were later injected with 125I-labeled T84.66 F(ab')2. Peritoneal tumors were localized by RIGS 5 days after antibody injection. The minimum number of cells detected by a gamma probe was assayed by in vitro tumor cell localization. RESULTS: We observed 37 peritoneal metastases: 8 invisible (long diameter, <1 mm), 6 small (1- < 5 mm), and 23 large (> or =5 mm) tumors. The accuracy, sensitivity and specificity of RIGS in detecting peritoneal metastasis were 82% (69/84), 76% (28/37), and 87% (41/47), respectively. RIGS accuracy did not differ with respect to tumor diameter. Mean labeling indices over minimal and maximal normal counts were 6.1+/-1.2 (mean +/- SEM) and 4.7+/-1, respectively. Mean scores of CEA immunostaining and silver grains in tumors were significantly higher than those in the nontumor-bearing peritoneum (P < 0.001). There was a close correlation among radioactivity, immunostaining and microautoradiography (P < 0.001-0.005). We observed six false-positive and nine false-negatives which may have been due to high blood background and negative radioimmune reactivity, respectively. CONCLUSIONS: 125I-labeled T84.66 F(ab')2 efficiently targeted peritoneally disseminated gastric cancer cells, suggesting that RIGS using this immune agent may accurately detect occult peritoneal metastases in patients with gastric cancer.

Characterization of mutator phenotype in familial colorectal cancer patients not fulfilling amsterdam criteria.

PURPOSE: Although the mutator phenotype, including genetic and epigenetic alterations of the mismatch repair (MMR) system, seems to be pronounced in familial colorectal cancer, there have been few integrative studies comprising the entire mutator pathway. This study was done to identify the entire mutator pathway determining risk factors in patients with familial colorectal cancer not fulfilling the Amsterdam criteria. EXPERIMENTAL DESIGN: We consecutively recruited 134 colorectal cancer patients with a family history of accompanying cancers. Patients with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria, familial adenomatous polyposis, or those receiving preoperative radiotherapy were excluded. Mutator phenotype was assessed by assaying microsatellite instability (MSI) at 24 markers, hMLH1-promoter methylation, mutations at MMR genes (hMLH1, hMSH2, hMSH6, and hPMS2), and immune staining of MMR proteins (hMLH1, hMSH2, hMSH6, hPMS1, and hPMS2). RESULTS: Of the 208 cancers in first-degree and/or second-degree relatives of patients, colorectal and gastric cancers (81%) were most common. Of the 134 proband colorectal cancers, 23 (17%) were MSI in high level, and 32 (24%) were MSI in low level. MMR alterations, including known polymorphism and splicing substitution, were identified in eight patients (6%). Twenty-eight tumors with mutator phenotype were further identified by hMLH1-promoter methylation and/or loss of MMR protein expression. In 51 tumors (38%), mutator phenotype was associated with right-sided colon cancer (P < 0.001) and younger age at onset (P=0.032), but the number of patients with a mutator phenotype did not differ with respect to inheritance patterns of accompanying cancers, either successive or horizontal transmission (P=0.815). Familial impact value, which differentially associated the degree of relatives with all accompanying cancers, effectively discriminated MSI in high level from microsatellite stable/MSI in low level tumors. CONCLUSION: Familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers inherited by dominant or recessive transmission. MMR gene mutations, however, are less associated with mutator phenotype in familial colorectal cancer.

Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients.

The genotypic consequences of numerous single-nucleotide variants in human mismatch repair genes are mostly undetermined. We examined 27 reported single-nucleotide variants, rarely or ambiguously verified in a population-based study, to identify single-nucleotide polymorphisms (SNPs), haplotypes, and the genotype-phenotype association in Korean populations of 330 healthy individuals, 107 sporadic colorectal cancer patients, and 107 of their first-degree relatives. Real-time PCR 5'-nuclease assays (TaqMan) MGB assay) were used to determine 24 single-nucleotide variants, and restriction fragment length polymorphism (RFLP) assays were used to determine 3 variants. Of these 27 variants, 4 (hMSH2 gIVS12-6, hMLH1 655, hMLH1 1151, and hMSH2 1168, in descending order) were identified as SNPs occurring in 4.5 to 53.1% of healthy individuals, with polymorphism levels of 0.023-0.3 (mean, 0.092). East Asian populations had an ethnic predilection for the hMLH1 1151 SNP. The genotype distribution for all four SNPs showed no association with sporadic colorectal cancer. Twenty-three variants were not identified in the Korean population, suggesting that fifteen of these variants are colorectal cancer-related mutations and eight are SNPs. Two haplotype patterns existed exclusively, but with rare frequency, in sporadic colorectal cancer patients. The hMLH1 655 allele was closely correlated with hMLH1 protein expression (P = 0.02), but none of the four SNPs was associated with clinicopathologic variables. Among the 27 single nucleotide variants of mismatch repair genes, 12 were suggestive of nonfunctional SNPs and 15 may be colorectal cancer-related mutations. Further verification in other ethnic groups may provide the genotypic and phenotypic significance of single nucleotide variants found in mismatch repair genes.

Efficient targeting of gastric cancer cells using radiolabeled anti-carcinoembryonic antigen-specific T84.66 fragments in experimental radioimmunoguided surgery.

BACKGROUND: Radioimmunoguided surgery (RIGS) appears as an efficient tool for accurate tumor detection up to the level of micrometastases by detecting radiolabeled antibody-bound tumor cells during operation. Anti-CEA-specific T84.66 fragments were examined as to whether they efficiently detected gastric cancer cells in experimental RIGS. T84.66, anti-CEA-specific antibody, has widely been used as an immune carrier in the preclinical and clinical trials of radioimmunotherapy and radioimmunoscintiscan. MATERIALS AND METHODS: Fifty-one tumors from two human gastric carcinoma cell lines with profuse (MKN45) and low (RF48) CEA expression were successfully implanted subcutaneously in the backs of 32 nude mice. Tumors were localized after 125I-labeled T84.66 F(ab')2 and Fab' injection. RESULTS: The radioactivity of F(ab')2-pretreated mice was greater than that of Fab'-pretreated in all organs and tumors (p<0.001-0.035). Localization indices of the tumor in various organs revealed 7.4 to 32.5 in F(ab')2-pretreated and 1 to 7.1 in Fab'-pretreated mice. Silver grains and immune staining were predominantly distributed in tumor cells regardless of fragment types and cell lines. There was no false-negative evaluation of tumor in F(ab')2-pretreated mice. Sensitivity and specificity of tumor localization by RIGS were the highest in the F(ab')2-pretreated mice (95% for MKN45- and 82% for RF46-xenografted mice) and the least in the Fab'-pretreated mice (66% for MKN45- and 67% for RF46-xenografted mice). In all organs, three quarters of the false-positive evaluations occurred from silver grains as radioimmune complex or dissociated nuclides in the circulation that can be eliminated with time. CONCLUSION: Anti-CEA-specific T84.66 fragments achieved a great affinity and avidity with accurate localization of gastric carcinoma in experimental RIGS.